Frances Tiafoe set up a US Open semi-final against Taylor Fritz to guarantee there will be an American man in the singles final in New York for the first time in 18 years.
Andy Roddick was the last American man to win a Grand Slam singles title when he triumphed at Flushing Meadows in 2003.
Roddick was also the last American man to reach a US Open final, having lost to Roger Federer there in 2006.
But the wait for a home finalist will soon be over after Fritz ended his run of Grand Slam quarter-final disappointment by edging out Alexander Zverev 7-6 (7-2) 3-6 6-4 7-6 (7-3).
The ever-entertaining Tiafoe then advanced when opponent Grigor Dimitrov was forced to retire injured.
Tiafoe led Dimitrov 6-3 6-7 (5-7) 6-3 4-1 when the Bulgarian, hampered by an apparent hamstring injury, ended the match.
"I didn't want to end it like that, for me or the crowd. But Friday is going to be one hell of a day," 20th seed Tiafoe said.
"It's the biggest match of mine and Taylor's life."
It is a third major semi-final for Tiafoe and a first for Fritz, who had lost all four of his previous matches at this stage of a major.
He roared in delight after battling past German fourth seed and 2020 runner-up Zverev earlier on Tuesday.
"Today just felt different," Fritz, 26, said.
"I really felt like it was my time to go a step further. It's only fitting I'm doing it here on this court, at the Open, in front of this crowd."
Fritz's victory followed New Yorker Emma Navarro beating Paula Badosa to reach the semi-finals of the women's singles.
Taylor Fritz's biggest title to date is the Indian Wells crown in 2022
This has proved to be Fritz's breakthrough moment in his 33rd Grand Slam appearance.
He lost to Novak Djokovic in the US Open quarter-finals in 2023, fell in the last eight at Wimbledon in 2022 and July this year and suffered defeat in the Australian Open quarters in January.
After sharing two tight sets, the crucial moment came deep in the third when Zverev looked to have the momentum, having recovered an early break.
He missed a straightforward backhand on break point at 4-4 which allowed Fritz to hold and then the fourth seed offered up three forehand errors to fall 0-40 behind.
Zverev held off those three set points but Fritz eventually broke through at the fifth attempt.
Fritz, who also beat Zverev from two sets down at Wimbledon this year, was able to neutralise the German's booming first serve and remain the more solid with the finish line in sight while hitting powerful serves of his own.
He gained the initiative in the fourth-set tie-break by taking the first point on the Zverev serve and won a gruelling 24-point rally for the second break and a 5-2 lead.
Fritz faltered momentarily, pushing a nervous forehand wide, but Zverev offered up two more errors to seal the result.
Zverev said afterwards it was the most angry and disappointed he had felt after a match in a "long time".
“I played terrible," said Zverev, who was unusually flat in the final set and complained about his racquet throughout as he chased a first Grand Slam title and a third US Open semi-final.
"I just have no answers right now. He played quite a good match. I did nothing to deserve to win.”
On the prospect of an all-American semi-final against Tiafoe, Fritz said: "I know the crowd would really want to see me play Frances so we get an American in the final. That could be crazy."
Britain's Jack Draper is among those remaining in the top half of the draw. He plays Alex de Minaur in the quarter-final on Wednesday.
Tiafoe’s previous Slam semi-final appearance was also in New York, where he so often produces his best tennis by feeding off an animated crowd, while his dynamic, attacking style helps ratchet up the volume further.
Roared on by a partisan crowd, Tiafoe was on the front foot immediately to put pressure on the Dimitrov serve.
The first break came midway through the opening set and there was little jeopardy as the American closed it out.
Dimitrov had been oddly passive and quickly went a break down in the second but, urged on by coach Jamie Delgado, he backed his shot-making and was rewarded.
He rescued the break and an electric end to the second set saw the pair go shot for shot in the tie-break.
It came to an almost comical conclusion as, having earned three set points, Dimitrov double-faulted twice, only for Tiafoe to hand him the third with a double fault of his own.
The match remained in the balance until an injury to Dimitrov suddenly turned it into a procession.
With his opponent clearly struggling, Tiafoe professionally and respectfully stuck to the task at hand before a tearful Dimitrov admitted defeat.
"Obviously, it's not the way I wanted to get through but being in another semi-final here is incredible," Tiafoe said afterwards.